Optimal primary surgical treatment for advanced epithelial ovarian cancer

 

Abstract

Background

Ovarian cancer is the sixth most common cancer among women. In addition to diagnosis and staging, primary surgery is performed to achieve optimal cytoreduction (surgical efforts aimed at removing the bulk of the tumour) as the amount of residual tumour is one of the most important prognostic factors for survival of women with epithelial ovarian cancer. An optimal outcome of cytoreductive surgery remains a subject of controversy to many practising gynae-oncologists. The Gynaecologic Oncology group (GOG) currently defines 'optimal' as having residual tumour nodules each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, it is unclear whether it is the surgical procedure that is directly responsible for the superior outcome that is associated with less residual disease.

Objectives

To evaluate the effectiveness and safety of optimal primary cytoreductive surgery for women with surgically staged advanced epithelial ovarian cancer (stages III and IV).

To assess the impact of various residual tumour sizes, over a range between zero and 2 cm, on overall survival.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3) and the Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE and EMBASE (up to August 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.

Selection criteria

Retrospective data on residual disease from randomised controlled trials (RCTs) or prospective and retrospective observational studies which included a multivariate analysis of 100 or more adult women with surgically staged advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery followed by adjuvant platinum-based chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm.

Data collection and analysis

Two review authors independently abstracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis.

Main results

There were no RCTs or prospective non-RCTs identified that were designed to evaluate the effectiveness of surgery when performed as a primary procedure in advanced stage ovarian cancer.

We found 11 retrospective studies that included a multivariate analysis that met our inclusion criteria. Analyses showed the prognostic importance of complete cytoreduction, where the residual disease was microscopic that is no visible disease, as overall (OS) and progression-free survival (PFS) were significantly prolonged in these groups of women. PFS was not reported in all of the studies but was sufficiently documented to allow firm conclusions to be drawn.

When we compared suboptimal (> 1 cm) versus optimal (< 1 cm) cytoreduction the survival estimates were attenuated but remained statistically significant in favour of the lower volume disease group There was no significant difference in OS and only a borderline difference in PFS when residual disease of > 2 cm and < 2 cm were compared (hazard ratio (HR) 1.65, 95% CI 0.82 to 3.31; and HR 1.27, 95% CI 1.00 to 1.61, P = 0.05 for OS and PFS respectively).

There was a high risk of bias due to the retrospective nature of these studies where, despite statistical adjustment for important prognostic factors, selection bias was still likely to be of particular concern.

Adverse events, quality of life (QoL) and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies.

Authors' conclusions

During primary surgery for advanced stage epithelial ovarian cancer all attempts should be made to achieve complete cytoreduction. When this is not achievable, the surgical goal should be optimal (< 1 cm) residual disease. Due to the high risk of bias in the current evidence, randomised controlled trials should be performed to determine whether it is the surgical intervention or patient-related and disease-related factors that are associated with the improved survival in these groups of women. The findings of this review that women with residual disease < 1 cm still do better than women with residual disease > 1 cm should prompt the surgical community to retain this category and consider re-defining it as 'near optimal' cytoreduction, reserving the term 'suboptimal' cytoreduction to cases where the residual disease is > 1 cm (optimal/near optimal/suboptimal instead of complete/optimal/suboptimal).

 

Plain language summary

Clear survival benefit is achieved if all or most (< 1 cm remaining) of the tumour after primary surgical treatment for advanced epithelial ovarian cancer is removed

Ovarian cancer is a cancerous growth arising from different parts of the ovary. It is the sixth most common cancer among women. Most ovarian cancers are classified as epithelial. Ovarian epithelial cancer is a disease in which malignant (cancer) cells form in the tissue covering the ovary and most cases are epithelial. Primary surgery is performed to achieve optimal cytoreduction (surgical efforts aiming at removing the bulk of the tumour) as the amount of tumour that remains after surgery (residual disease) is one of the most important factors that is taken into account when determining a prognosis (prognostic factor) for survival of epithelial ovarian cancer. Optimal cytoreductive surgery remains a subject of controversy to many practising obstetric gynaecologists who specialise in the diagnosis and treatment of women with cancer of the reproductive organs (gynae-oncologists). The Gynaecologic Oncology Group (GOG) currently defines 'optimal' as having a small aggregation of remaining cancer cells after surgery (residual tumour nodules) each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, there is limited evidence to support the conclusion that the surgical procedure is directly responsible for the superior outcome associated with less residual disease. This review assessed overall and progression-free survival of optimal primary cytoreductive surgery for women with advanced epithelial ovarian cancer (stages III and IV). We found 11 retrospective studies that included more than 100 women and used a multivariate analysis (used statistical adjustment for important prognostic factors) and met our inclusion criteria. Analyses showed the prognostic importance of complete cytoreduction, where the residual disease is microscopic with no visible disease, as overall (OS) and progression-free survival (PFS) were significantly prolonged in these groups of women. PFS was not reported in all of the studies but was sufficiently documented to allow firm conclusions to be drawn. When we compared suboptimal (> 1 cm) versus optimal (< 1 cm) cytoreduction the survival estimates were attenuated but remained statistically significant in favour of the lower volume disease group, but there was no significant difference in OS and only a borderline difference in PFS when residual disease of > 2 cm and < 2 cm were compared. There was a high risk of bias due to the retrospective nature of these studies. Adverse events, quality of life (QoL) and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies. During primary surgery for advanced stage epithelial ovarian cancer, all attempts should be made to achieve complete cytoreduction. When this is not achievable, the surgical goal should be optimal (< 1 cm) residual disease. Due to the high risk of bias in the current evidence, randomised controlled trials should be performed to determine whether it is the surgical intervention or patient-related and disease-related factors that are associated with the improved survival in these groups of women.

 

Resumen

Antecedentes

Tratamiento quirúrgico primario óptimo para el cáncer epitelial de ovario avanzado

El cáncer de ovario es el sexto cáncer más frecuente en las mujeres Además de para el diagnóstico y la estadificación, la cirugía primaria se realiza para lograr la citorreducción óptima (el esfuerzo quirúrgico tiene como objetivo extraer la mayor parte del tumor) debido a que la cantidad de tumor residual es uno de los factores pronósticos más importantes para la supervivencia de las mujeres con cáncer epitelial de ovario. Aún es motivo de controversia el resultado óptimo de la cirugía citorreductora para muchos ginecólogos oncólogos en ejercicio. Actualmente el Gynaecologic Oncology Group (GOG) define “óptimo” como la presencia de nódulos tumorales residuales que midan cada uno 1 cm o menos en su diámetro máximo, y la citorreducción completa (enfermedad microscópica) es el resultado quirúrgico ideal. Aunque el tamaño de las masas tumorales residuales después de la cirugía ha mostrado ser un factor pronóstico importante para el cáncer ovárico avanzado, no está claro si el procedimiento quirúrgico es el responsable directo del resultado superior que se asocia con menos enfermedad residual.

Objetivos

Evaluar la efectividad y la seguridad de la cirugía citorreductora primaria óptima para las mujeres con cáncer epitelial de ovario avanzado con estadificación quirúrgica (estadios III y IV).

Evaluar la repercusión de diversos tamaños tumorales residuales, en un rango de cero a 2 cm, sobre la supervivencia global.

Estrategia de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (Cochrane Library 2010, número 3) y en el Registro Especializado de Ensayos Controlados del Grupo de Revisión Cochrane de Cáncer Ginecológico (Cochrane Gynaecological Cancer Review Group), MEDLINE y EMBASE (hasta agosto 2010). También se buscó en los registros de ensayos clínicos, los resúmenes de reuniones científicas, las listas de referencias de los estudios incluidos y se estableció contacto con expertos en el campo.

Criterios de selección

Datos retrospectivos sobre la enfermedad residual de ensayos controlados con asignación aleatoria (ECAs) o estudios observacionales prospectivos y retrospectivos que incluyeron un análisis multivariado de 100 o más mujeres adultas con cáncer epitelial de ovario avanzado con estadificación quirúrgica y a las que se les realizó cirugía citorreductora primaria seguida de quimioterapia adyuvante con platino. Sólo se incluyeron los estudios que definieron la citorreducción óptima como la cirugía que dio lugar a tumores residuales con un diámetro máximo de cualquier umbral hasta 2 cm.

Obtención y análisis de los datos

Dos revisores extrajeron los datos y evaluaron el riesgo de sesgo de forma independiente. Cuando fue posible, los datos se resumieron en un metanálisis.

Resultados principales

No se identificaron ECAs ni ensayos controlados sin asignación aleatoria prospectivos diseñados para evaluar la efectividad de la cirugía cuando se realizó como procedimiento primario en el cáncer de ovario en estadio avanzado.

Se encontraron 11 estudios retrospectivos que incluyeron un análisis multivariado que cumplió los criterios de inclusión. Los análisis mostraron la importancia pronóstica de la citorreducción completa donde cuando la enfermedad residual fue microscópica, es decir, no había enfermedad visible, ya que la supervivencia general (SG) y la supervivencia libre de progresión (SLP) se prolongaron significativamente en estos grupos de mujeres. La SLP no se informó en todos los estudios pero se documentó de forma suficiente para permitir establecer conclusiones definitivas.

Cuando se comparó la citorreducción subóptima (> 1 cm) versus óptima (< 1 cm) las estimaciones de supervivencia se atenuaron pero permanecieron estadísticamente significativas a favor del grupo con enfermedad de volumen inferior. No hubo diferencias significativas en la SG y sólo una diferencia marginal en la SLP cuando se compararon la enfermedad residual > 2 cm y < 2 cm (cociente de riesgos instantáneos [CRI] 1,65, IC del 95%: 0,82 a 3,31; y CRI 1,27, IC del 95%: 1,00 a 1,61; p = 0,05 para la SG y la SLP respectivamente).

Hubo un alto riesgo de sesgo debido a la naturaleza retrospectiva de estos estudios donde, a pesar del ajuste estadístico por factores pronósticos importantes, el sesgo de selección todavía es probable que sea una inquietud particular.

Los eventos adversos, la calidad de vida (CdV) y la relación costeefectividad no se informaron por brazo de tratamiento ni a un nivel satisfactorio en cualquiera de los estudios.

Conclusiones de los autores

Durante la cirugía primaria del cáncer epitelial de ovario en estadio avanzado se deben hacer todos los intentos para lograr la citorreducción completa. Cuando no es posible lograr lo anterior el objetivo quirúrgico debe ser la enfermedad residual óptima (< 1 cm). Debido al alto riesgo de sesgo en las pruebas actuales se deben realizar ensayos controlados con asignación aleatoria para determinar si es la cirugía o los factores relacionados con las pacientes y con la enfermedad los que se asocian con la mejoría en la supervivencia en estos grupos de mujeres. Los hallazgos de esta revisión de que a las mujeres con enfermedad residual < 1 cm les va aún mejor que a las mujeres con enfermedad residual > 1 cm deben estimular a la comunidad quirúrgica a mantener esta categoría y a considerar la posibilidad de redefinirla como citorreducción “casi óptima” y reservar el término citorreducción “subóptima” para los casos donde la enfermedad residual es > 1 cm (óptima / casi óptima / subóptima en lugar de completa / óptima / subóptima).

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano